High-Resolution Genomic Profiling of Liver Cancer Links Etiology With Mutation and Epigenetic Signatures.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a model of a diverse spectrum of cancers because it is induced by well-known etiologies, mainly hepatitis C virus (HCV) and hepatitis B virus. Here, we aimed to identify HCV-specific mutational signatures and explored the link between the HCV-related regional variation in mutations rates and HCV-induced alterations in genome-wide chromatin organization. METHODS: To identify an HCV-specific mutational signature in HCC, we performed high-resolution targeted sequencing to detect passenger mutations on 64 HCC samples from 3 etiology groups: hepatitis B virus, HCV, or other. To explore the link between the genomic signature and genome-wide chromatin organization we performed chromatin immunoprecipitation sequencing for the transcriptionally permissive H3K4Me3, H3K9Ac, and suppressive H3K9Me3 modifications after HCV infection. RESULTS: Regional variation in mutation rate analysis showed significant etiology-dependent regional mutation rates in 12 genes: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, and ARSD. We found an enrichment of C->T transversion mutations in the HCV-associated HCC cases. Furthermore, these cases showed regional variation in mutation rates associated with genomic intervals in which HCV infection dictated epigenetic alterations. This signature may be related to the HCV-induced decreased expression of genes encoding key enzymes in the base excision repair pathway. CONCLUSIONS: We identified novel distinct HCV etiology-dependent mutation signatures in HCC associated with HCV-induced alterations in histone modification. This study presents a link between cancer-causing mutagenesis and the increased predisposition to liver cancer in chronic HCV-infected individuals, and unveils novel etiology-specific mechanisms leading to HCC and cancer in general.

Preparedness for Mass Casualty Incidents: The Effectiveness of Current Training Model.

The importance of MCI organization and training was highlighted by the events of September 11, 2001. Training focuses on the management of physical injuries caused by a single traumatic event over a well-defined, relatively short timeframe. MCI management is integrated into surgical and trauma training, with disaster management training involving the emergency services, law enforcement, and state infrastructure agencies. The COVID-19 pandemic revealed gaps in the preparedness of nation states and global partners in disaster management. The questions that arose include 'has training really prepared us for an actual emergency,' 'what changes need to be made to training to make it more effective,' and 'who else should training be extended to?' This article focuses on the importance of involving multiple sectors in mass casualty training and asks whether greater involvement of non-medical agencies and the public, in operational drills might improve preparedness for global events such as the COVID-19 pandemic.

Case Report: Robotically Assisted Excision of Cystic Tumor Located in a Difficult to Access Area in the Liver.

Introduction: Cystic liver lesions may be benign cysts, parasitic infestations, or malignant tumors requiring surgical resection. Hilar location and relation to major vasculature present challenges in conventional surgical access and resection. Materials and Methods: We describe totally robotic excision of a cystadenoma in a 55-year-old woman without complication. Time points in the accompanying video (https://youtu.be/Tn_QPgpSHA4) are embedded within the text. Results: Advantages of the robotic technique lie in overcoming the natural restriction of conventional laparoscopic instruments, easier repair, and control of intraoperative vascular injuries using EndoWrist® instruments, ergonomic dissection close to major vasculature and reduced intraoperative blood loss as dissection is easier. Discussion: Indications for robotic surgery included the large size of the cystic lesion, its intrahepatic location, and compression of the inferior vena cava (IVC) and right and middle hepatic veins. Had robotic removal of the lesion not been feasible, the entire lobe of the liver would have required resection.

Assessment of Global Health Education: The Role of Multiple-Choice Questions.

Introduction: The standardization of global health education and assessment remains a significant issue among global health educators. This paper explores the role of multiple choice questions (MCQs) in global health education: whether MCQs are appropriate in written assessment of what may be perceived to be a broad curriculum packed with fewer facts than biomedical science curricula; what form the MCQs might take; what we want to test; how to select the most appropriate question format; the challenge of quality item-writing; and, which aspects of the curriculum MCQs may be used to assess. Materials and Methods: The Medical School for International Health (MSIH) global health curriculum was blue-printed by content experts and course teachers. A 30-question, 1-h examination was produced after exhaustive item writing and revision by teachers of the course. Reliability, difficulty index and discrimination were calculated and examination results were analyzed using SPSS software. Results: Twenty-nine students sat the 1-h examination. All students passed (scores above 67% - in accordance with University criteria). Twenty-three (77%) questions were found to be easy, 4 (14%) of moderate difficulty, and 3 (9%) difficult (using examinations department difficulty index calculations). Eight questions (27%) were considered discriminatory and 20 (67%) were non-discriminatory according to examinations department calculations and criteria. The reliability score was 0.27. Discussion: Our experience shows that there may be a role for single-best-option (SBO) MCQ assessment in global health education. MCQs may be written that cover the majority of the curriculum. Aspects of the curriculum may be better addressed by non-SBO format MCQs. MCQ assessment might usefully complement other forms of assessment that assess skills, attitude and behavior. Preparation of effective MCQs is an exhaustive process, but high quality MCQs in global health may serve as an important driver of learning.

Advancing global health through engineering: a perspective on teaching an online global health course to engineers during a global pandemic.

BACKGROUND: The effect of the COVID-19 pandemic on higher education has been felt worldwide. There are many lessons to be learned about teaching and learning in the digital age. While we evaluate the full impact and prepare ourselves for the new normal, it is worth reflecting on some of the positive aspects of online teaching and learning and understanding how students, teachers and the wider faculty have been able to support each other through the challenges of the pandemic. In this article, we offer a perspective on teaching an online Global Health course to engineering students. RESULTS: The course, taught by a physician, provides a grounding in basic medical, scientific and engineering principles and is available to students of diverse engineering specialties. Students developed skills and gained confidence in active listening, sourcing and critical appraisal of information, interdisciplinary teamwork, needs assessment, problem analysis, problem-solving, effective communication, and organisation and delivery of information (in English). Students learned the importance of engineering in landmark historical public health projects, the delivery of modern health care, and the pressing need to develop engineering solutions to current global health problems. Course assessment was formative: 20% attendance and active participation in online classes, 30% problem-solving, 30% student presentations, and 20% written abstracts for two class projects: historical innovations and medicine in the future. CONCLUSIONS: We show how, through conversion from a classroom to an online format, we were able to deliver a rich curriculum with sound assessment where students were able to innovate together and discover the importance of engineering in health and well-being as we all experience an unprecedented global health pandemic.

Case Report: Delayed Primary Wound Closure After Extensive Abdominal Wall Resection for Infection and Malignancy Using TopClosure®.

The closure of a massive abdominal wall defect is illustrated using a novel dynamic closure technique - the TopClosure® tension relief system. This system attaches to the abdominal wall immediately after laparotomy and allows for early approximation of the skin, avoiding an open abdomen and the complications associated with this. The technique in this case was employed after extensive resection of the abdominal wall for infected skin metastases of colonic adenocarcinoma and circumvented post-operative ventilation and open abdomen. Early recovery after such extensive surgery is important in terms of patient morbidity and mortality. In this case, primary surgery may not have been an acceptable risk to undertake without the option of Top Closure of the abdomen. We illustrate the technique of abdominal wall closure through a series of images of the procedure.

Case Report: Robotic ALPPS Procedure for Hepatocellular Carcinoma in the Right Lobe of the Liver.

Introduction: Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) is a surgical procedure for liver malignancy where the volume of the liver remnant is estimated to be too small. We present the first case of two-stage robotic ALPPS procedure, illustrating the steps and advantages of robotic surgery. Materials and Methods: A 68-year-old man with morbid obesity (BMI 40), portal fibrosis, macrovesicular steatosis, and poor liver function underwent robotic ALPPS for hepatocellular carcinoma in the right lobe of the liver (segments 5, 7, and 8). A video presentation (https://youtu.be/M50Gumf-4pw) of the operative procedure is accompanied by explanation in the text with embedded corresponding video time points. Results: Both stages of the procedure were performed robotically, with negligible blood loss, and rapid surgical recovery. The patient died 3 years later. Discussion: Robotic ALPPS offers reduced morbidity in major liver surgery for malignancy and may extend survival in meticulously selected patients.

Implementing a Practical Global Health Curriculum: The Benefits and Challenges of Patient-Based Learning in the Community.

Background: A growing number of medical schools across the world have incorporated global health (GH) into their curricula. While several schools focus GH education on lecture-based courses, our premise is that global health education should embody a holistic approach to patient care and medical education in local communities. Medical students may learn global health by focusing on real patients, their families and communities as part of a practical curriculum. Aims and Objectives: A unique GH curriculum was devised to compare student learning outcomes on a practical vs. lecture-based course. The premise was that learning from patients would result in a greater breadth of coverage of the global health syllabus as compared to that from a lecture-based course. Methods: A teaching and learning program was developed over 3 years to provide medical students interaction with real patients in the community on a first-preclinical-year Introduction to Global Health and Medical Anthropology course. Learning outcomes on the practical vs. lecture-based course were compared using thematic analysis of the written assignments of both courses: global health case reports and literature reviews, respectively. All members of three cohorts of students undertaking the course in successive academic years were compared (Group A: literature review; Groups B and C: case reports; n = 87). Results: Case reports provided evidence of a greater breadth of learning outcomes when compared to the literature review (p < 0.001). The writing of the case report was enhanced by completion of a field journal and family health needs assessment tool (p < 0.001). Students demonstrated a closeness to their patients that added depth, understanding and motivation to assist patients in health activities and advocate for their needs. Discussion: Placements with patients in the community provided students with a rich learning environment and facilitated the formation of relationships with patients to better understand the social determinants of health and advocate for improvements in their living and working conditions and access to healthcare. Conclusions: Global health may be better learned experientially by following patients rather than from frontal lectures. Patient-based learning inspires a commitment to the individual and facilitates medical schools in meeting their obligations to the communities they serve.

Applying the Delphi process for development of a hepatopancreaticobiliary robotic surgery training curriculum.

BACKGROUND: Robotic hepatopancreaticobiliary (HPB) procedures are performed worldwide and establishing processes for safe adoption of this technology is essential for patient benefit. We report results of the Delphi process to define and optimize robotic training procedures for HPB surgeons. METHODS: In 2019, a robotic HPB surgery panel with an interest in surgical training from the Americas and Europe was created and met. An e-consensus-finding exercise using the Delphi process was applied and consensus was defined as 80% agreement on each question. Iterations of anonymous voting continued over three rounds. RESULTS: Members agreed on several points: there was need for a standardized robotic training curriculum for HPB surgery that considers experience of surgeons and based on a robotic hepatectomy includes a common approach for "basic robotic skills" training (e-learning module, including hardware description, patient selection, port placement, docking, troubleshooting, fundamentals of robotic surgery, team training and efficiency, and emergencies) and an "advanced technical skills curriculum" (e-learning, including patient selection information, cognitive skills, and recommended operative equipment lists). A modular approach to index procedures should be used with video demonstrations, port placement for index procedure, troubleshooting, and emergency scenario management information. Inexperienced surgeons should undergo training in basic robotic skills and console proficiency, transitioning to full procedure training of e-learning (video demonstration, simulation training, case observation, and final evaluation). Experienced surgeons should undergo basic training when using a new system (e-learning, dry lab, and operating room (OR) team training, virtual reality modules, and wet lab; case observations were unnecessary for basic training) and should complete the advanced index procedural robotic curriculum with assessment by wet lab, case observation, and OR team training. CONCLUSIONS: Optimization and standardization of training and education of HPB surgeons in robotic procedures was agreed upon. Results are being incorporated into future curriculum for education in robotic surgery.

The Incidence of Road Traffic Crashes Among Young People Aged 15-20 Years: Differences in Behavior, Lifestyle and Sociodemographic Indices in the Galilee and the Golan.

Background: Adolescent injuries and fatalities constitute a world health concern and present a major public health burden. Of all childhood injuries in Israel 61.8% occur during road traffic crashes. The risk of being injured or killed in a road traffic crash is especially high among individuals deemed to have a low socio-economic status, but, there also exist crucial risk factors for road traffic crashes that are intrinsic social determinants of health, including behavior, lifestyle, education and employment. These associations are explored in this study. Aim: To examine the contribution of socioeconomic inequalities to the incidence of road traffic crashes among adolescents living in the Galilee and the Golan. Methods: A large retrospective study of trauma records (N = 3293) of 15-20-year-old patients who were injured in road traffic crashes and admitted to Ziv Medical Center between 2004 and 2015 was performed. These patients were subcategorized according to their home address. Using census data and other databases associations between socioeconomic inequalities, intrinsic social determinants and the prevalence of road crashes were investigated. Results: Road traffic crashes in the Galilee and the Golan are more frequent among residents of low socioeconomic areas. Fifty-five percent of drivers are from the areas of lowest socioeconomic level (levels 2 to 4) and are responsible for 60% of the road traffic injuries admitted to Ziv Medical Center (p < 0.001). In contrast, 42% of drivers are from areas of medium socioeconomic level (levels 5 and 6) but are responsible for only 35% of road traffic injuries (p < 0.001). Young women in the Galilee and the Golan are less likely to be involved in road traffic crashes-35.8% compared to 64.2% in young men. Conclusions: This research has shown that youth, male gender, socioeconomic status, education level and the quality of road infrastructure are important factors in the incidence of road traffic crashes in the Galilee and the Golan. This should be taken into consideration by policy makers in order to develop appropriate interventions in road safety targeted at multiple levels.

Team preparation for human uterus transplantation: Autologous transplantation in sheep model.

We performed autologous uterus transplantation using the living-sheep donor model for team preparation before human uterine transplantation. Five sequential operations (in 3 ewes) were prospectively conducted. Surgical technique included uterus retrieval, graft preparation, and uterus transplantation. Anastomoses were performed at the level of the external iliac. At 3-week follow-up, the uterus and anastomoses were checked for strictures and thrombosis. Two successful auto-transplantations were made, and one failed because of undeveloped uterine arteries (< 1 mm in diameter). In the first two ewes, we identified and used a deep, separate uterine vein, which was not described in other publications. In the third ewe, we used the utero-ovarian vein. The team was able to perform safe dissection and auto-transplantation, with no signs of strictures or thrombosis after 3 weeks. Cold ischemic time was 60 minutes, and warm ischemic time was between 40 and 60 minutes, with no need for re-anastomoses. We noticed that using the deep uterine vein in the sheep model can anatomically simulate better the human uterine vein and the difficulty to approach it. To avoid using unsuitable vessels for anastomoses, the uterine transplantation protocol in humans should include imaging of the donor's uterine vessels.

Complications of dysgerminoma: meeting the health needs of patients in conflict zones.

A symptom of prolonged conflict is the destruction of infrastructure and healthcare systems. While the need for acute trauma services is obvious in conflict zones, patients with chronic diseases also require care. This report describes the clinical course of a young teenage girl with a large mid pelvic tumour originating from the left ovary and reaching the umbilicus. She presented with acute abdominal pain and underwent surgery in a healthcare facility within a conflict zone. She was then transferred to a neighbouring country for continuing care. The tumour is malignant. After further surgery, she required chemotherapy and will need ongoing surveillance. She has since returned to her home country. It is doubtful that she will be able to access all the care she needs. We describe her healthcare needs and discuss the disastrous effects of conflict on meeting the health needs of civilian populations in war zones.

Retrospective analysis of case series of patients with vascular war injury treated in a district hospital.

INTRODUCTION: As the Syrian civil war continues, medical care of the injured remains a priority for health facilities receiving casualties. Ziv Medical Centre, the closest hospital in Israel to the Syrian border, has received 500 casualties since February 2013. Seventeen of these patients had vascular injuries. This research reports the care of these seventeen patients and explores the challenges of treatment in patients with little antecedent clinical history and improvised initial care that may be complicated by delay to definitive care, sepsis and limb ischaemia. METHOD: Electronic and paper patient records were examined. Descriptive case series data are presented. RESULTS: Fifteen of the 17 patients were male. The mean age was 20 years (range 8-30 years). Causes of injury included gunshot wounds (4 patients), shrapnel (multi-fragment) injury (12 patients), and 1 patient was run over and dragged behind a car. The time from injury to transfer to definitive care ranged from 5h to 7 days (mean 43 h). All but one patient had associated non-vascular multiple-trauma. Thirteen patients presented with limb ischaemia. Four patients had arterio-venous fistula (AVF) or pseudoaneurysm. There were 5 upper and 10 lower limb major vascular injuries. Three patients had neck vessel injuries. All patients were investigated with CT angiography and underwent surgical or endovascular intervention. In 12 patients, 4 vessels were debrided and re-anastomosed and 13 vessels bypassed. Endovascular repair was performed in 4 patients. After initial revascularisation, 4 patients went on to amputation. There were no deaths. CONCLUSIONS: The injuries treated are heterogeneous, and reflect the range of high energy vascular trauma expected in conflict. The broad range of vascular solutions required to optimise outcomes, in particular, limb salvage, in turn, reflect the challenges of dealing with such injuries, especially within the context of sepsis, ischaemia and delay. As war continues, there is a pressing need to address the needs of patients with high energy injuries in austere environments where there is a dearth of health resources and where definitive care may be days away.

Pasireotide for malignant insulinoma.

UNLABELLED: Malignant insulinoma usually has a poor prognosis, as no efficient medical treatment is available. The somatostatin analogs octreotide and lanreotide have limited ability to control the hypoglycemic events. Pasireotide is a multi-receptor targeted somatostatin-analog with improved affinity for SSTR5. There is to date no reported treatment experience with this drug in such tumors. CASE DESCRIPTION: A 72-year-old patient with a G2 stage IV insulinoma, who underwent excision of the primary pancreatic tumor and multiple hepatic metastases, required further treatment for recurrent hypoglycemic events. The glycemic control achieved with pasireotide LAR was better compared with lanreotide and everolimus. However, none of these treatments showed tumor anti-proliferative effects. CONCLUSIONS: Pasireotide monthly injections achieved improved glycemic control in a patient with malignant insulinoma and recurrent hypoglycemic events compared with other medical treatments.