Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs. METHODS: Our previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case-control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis. RESULTS: As compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92. CONCLUSION: DNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers.

Met and Unmet Need for Pediatric Surgical Access in Uganda: A Country-Wide Prospective Analysis.

INTRODUCTION: Children's surgical access in low and low-middle income countries is severely limited. Investigations detailing met and unmet surgical access are necessary to inform appropriate resource allocation. MATERIALS AND METHODS: Surgical volume, outcomes, and distribution of pediatric general surgical procedures were analyzed using prospective pediatric surgical databases from four separate regional hospitals in Uganda. The current averted burden of surgical disease through pediatric surgical delivery in Uganda and the unmet surgical need based on estimates from high-income country data was calculated. RESULTS: A total of 8514 patients were treated at the four hospitals over a 6-year period corresponding to 1350 pediatric surgical cases per year in Uganda or six surgical cases per 100,000 children per year. The majority of complex congenital anomalies and surgical oncology cases were performed at Mulago and Mbarara Hospitals, which have dedicated pediatric surgical teams (P < 0.0001). The averted burden of pediatric surgical disease was 27,000 disability adjusted life years per year, which resulted in an economic benefit of approximately 23 million USD per year. However, the average case volume performed at the four regional hospitals currently represents 1% of the total projected pediatric surgical need. CONCLUSIONS: This investigation is one of the first to demonstrate the distribution of pediatric surgical procedures at a country level through the use of a prospective locally created database. Significant disease burden was averted by local pediatric and adult surgical teams, demonstrating the economic benefit of pediatric surgical care delivery. These findings support several ongoing strategies to increase pediatric surgical access in Uganda.

The Dimeglio Olecranon Method Is Reliable in Diverse, Contemporary Patients for Predicting Future Growth.

BACKGROUND: Growth assessment, which relies on a combination of radiographic and clinical markers, is an integral part of clinical decision-making in pediatric orthopaedics. The aim of this study is to evaluate the accuracy and reliability of the Diméglio skeletal age system using a modern cohort of pediatric patients. METHODS: A retrospective review was undertaken of all patients at a large tertiary pediatric hospital who had lateral forearm radiographs (before the age of 14 y for females and before 16 y for males). In addition, all of these patients had height measurements within 60 days of their forearm x-ray and a final height listed in their medical records. The x-rays were graded by 5 reviewers according to the Diméglio skeletal age system. Inter and intraobserver reliability was tested. RESULTS: One hundred forty-seven patients with complete radiographs and height data were evaluated by 5 observers ranging in experience from medical students to senior pediatric orthopaedic surgeons. The Diméglio system demonstrated excellent reliability across levels of training with an intraobserver correlation coefficient of 0.995 (95% CI, 0.991-0.997) and an interobserver correlation coefficient of 0.906 (95% CI, 0.857-0.943). When the Diméglio stage was paired with age and sex in a multivariable linear regression model predicting the percent of final height, the adjusted R2 was 78.7% (model P value <0.001), suggesting a strong relationship between the Diméglio stage (plus age and sex) and percent of final height. CONCLUSION: This unique approach to maturity assessment demonstrates that the Diméglio staging system can be used effectively in a modern, diverse patient population. LEVEL OF EVIDENCE: Level II; retrospective cohort study.

Academic Global Surgery Curricula: Current Status and a Call for a More Equitable Approach.

INTRODUCTION: We aimed to search the literature for global surgical curricula, assess if published resources align with existing competency frameworks in global health and surgical education, and determine if there is consensus around a fundamental set of competencies for the developing field of academic global surgery. METHODS: We reviewed SciVerse SCOPUS, PubMed, African Medicus Index, African Journals Online (AJOL), SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) and Bioline for manuscripts on global surgery curricula and evaluated the results using existing competency frameworks in global health and surgical education from Consortium of the Universities for Global Health (CUGH) and Accreditation Council for Graduate Medical Education (ACGME) professional competencies. RESULTS: Our search generated 250 publications, of which 18 were eligible: (1) a total of 10 reported existing competency-based curricula that were concurrent with international experiences, (2) two reported existing pre-departure competency-based curricula, (3) six proposed theoretical competency-based curricula for future global surgery education. All, but one, were based in high-income countries (HICs) and focused on the needs of HIC trainees. None met all 17 competencies, none cited the CUGH competency on "Health Equity and Social Justice" and only one mentioned "Social and Environmental Determinants of Health." Only 22% (n = 4) were available as open-access. CONCLUSION: Currently, there is no universally accepted set of competencies on the fundamentals of academic global surgery. Existing literature are predominantly by and for HIC institutions and trainees. Current frameworks are inadequate for this emerging academic field. The field needs competencies with explicit input from LMIC experts to ensure creation of educational resources that are accessible and relevant to trainees from around the world.

Methylation-based Cell-free DNA Signature for Early Detection of Pancreatic Cancer.

OBJECTIVES: The potential of DNA methylation alterations in early pancreatic cancer (PC) detection among pancreatic tissue cell-free DNA seems promising. This study investigates the diagnostic capacity of the 4-gene methylation biomarker panel, which included ADAMTS1, BNC1, LRFN5, and PXDN genes, in a case-control study. METHODS: A genome-wide pharmacoepigenetic approach identified ADAMTS1, BNC1, LRFN5, and PXDN genes as putative targets. Tissue samples including stage I-IV PC (n = 44), pancreatic intraepithelial neoplasia (n = 15), intraductal papillary mucinous neoplasms (n = 24), and normal pancreas (n = 8), and cell-free DNA, which was acquired through methylation on beads technology from PC (n = 22) and control patients (n = 10), were included. The 2-∆ct was the outcome of interest and underwent receiver operating characteristic analysis to determine the diagnostic accuracy of the panel. RESULTS: Receiver operating characteristic analysis revealed an area under the curve of 0.93 among ADAMTS1, 0.76 among BNC1, 0.75 among PXDN, and 0.69 among LRFN5 gene. The combination gene methylation panel (ADAMTS1, BNC1, LRFN5, and PXDN) had an area under the curve of 0.94, with a sensitivity of 100% and specificity of 90%. CONCLUSIONS: This methylation-based biomarker panel had promising accuracy for PC detection and warranted further validation in prospective PC surveillance trials.

Tips for Building a Community for Incoming Medical Students Virtually in the COVID-19 Era.

A sense of community benefits medical trainees by preserving mental well-being, nurturing collegiality and mentorship, and grounding ties with partnering organizations and services. Within medical school, building these support relationships often begins shortly after matriculation. In the current pandemic and the accompanying shift to a virtual class format, we believe that a dedicated effort to foster this sense of community is crucial for students who otherwise may feel untethered to their new learning environment. Here, we detail tips for building a medical school community virtually in the COVID-19 era between peers, within the school institution, and within the surrounding environment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01447-z.

Epigenetic signatures differentiate uterine and soft tissue leiomyosarcoma.

Leiomyosarcomas (LMS) are diverse, rare, and aggressive mesenchymal soft tissue sarcomas. Epigenetic alterations influence multiple aspects of cancer, however epigenetic profiling of LMS has been limited. The goal of this study was to delineate the molecular landscape of LMS for subtype-specific differences (uterine LMS (ULMS) vs soft tissue LMS (STLMS)) based on integrated analysis of DNA methylation and gene expression to identify potential targets for therapeutic intervention and diagnosis. We identified differentially methylated and differentially expressed genes associated with ULMS and STLMS using DNA methylation and RNA-seq data from primary tumors. Two main clusters were identified through unsupervised hierarchical clustering: ULMS-enriched cluster and STLMS-enriched cluster. The integrated analysis demonstrated 34 genes associated with hypermethylation of the promoter CpG islands and downregulation of gene expression in ULMS or STLMS. In summary, these results indicate that differential DNA methylation and gene expression patterns are associated with ULMS and STLMS. Further studies are needed to delineate the contribution of epigenetic regulation to LMS subtype-specific gene expression and determine the roles of the differentially methylated and differentially expressed genes as potential therapeutic targets or biomarkers.

Access to pediatric surgery delivered by general surgeons and anesthesia providers in Uganda: Results from 2 rural regional hospitals.

BACKGROUND: Significant limitations in pediatric surgical capacity exist in low- and middle-income countries, especially in rural regions. Recent global children's surgical guidelines suggest training and support of general surgeons in rural regional hospitals as an effective approach to increasing pediatric surgical capacity. METHODS: Two years of a prospective clinical database of children's surgery admissions at 2 regional referral hospitals in Uganda were reviewed. Primary outcomes included case volume and clinical outcomes of children at each hospital. Additionally, the disability-adjusted life-years averted by delivery of pediatric surgical services at these hospitals were calculated. Using a value of statistical life calculation, we also estimated the economic benefit of the pediatric surgical care currently being delivered. RESULTS: From 2016 to 2019, more than 300 surgical procedures were performed at each hospital per year. The majority of cases were standard general surgery cases including hernia repairs and intussusception as well as procedures for surgical infections and trauma. In-hospital mortality was 2.4% in Soroti and 1% in Lacor. Pediatric surgical capacity at these hospitals resulted in over 12,400 disability-adjusted life-years averted/year. This represents an estimated economic benefit of 10.2 million US dollars/year to the Ugandan society. CONCLUSION: This investigation demonstrates that lifesaving pediatric procedures are safely performed by general surgeons in Uganda. General surgeons who perform pediatric surgery significantly increase surgical access to rural regions of the country and add a large economic benefit to Ugandan society. Overall, the results of the study support increasing pediatric surgical capacity in rural areas of low- and middle-income countries through support and training of general surgeons and anesthesia providers.

Characterizing the social media footprint of general surgery residency programs.

BACKGROUND: The medical community has increasingly embraced social media for a variety of purposes, including trainee education, research dissemination, professional networking, and recruitment of trainees and faculty. Platform choice and usage patterns appear to vary by specialty and purpose, but few studies comprehensively assess programs' social media presence. Prior studies assessed general surgery departments' Twitter use but omitted additional social media platforms and residency-specific accounts. OBJECTIVE: This study sought to broadly characterize the social media footprint of U.S. general surgery residency programs. METHODS: Using a protocolized search of program websites, social media platforms (Twitter, Facebook, Instagram, LinkedIn), and internet search, cross-sectional data on social media usage in March 2020 were collected for programs, their affiliated departments, their program directors (PDs), and their assistant/associate PDs (APDs). RESULTS: 318 general surgery residency programs, 313 PDs, and 296 APDs were identified. 47.2% of programs had surgery-specific accounts on ≥1 platform. 40.2% of PDs and APDs had ≥1 account on Twitter and/or LinkedIn. Program type was associated with social media adoption and Twitter utilization, with lower usage among university-affiliated and independent programs (p<0.01). CONCLUSIONS: Most general surgery residencies, especially non-university-based programs, lacked any department or residency accounts across Twitter, Facebook, and Instagram by March 2020. These findings highlight opportunities for increased social media engagement and act as a pre-pandemic baseline for future investigations of how the shift to virtual trainee education, recruitment, conferences, and clinical care affect social media use.

Implementation of a contextually appropriate pediatric emergency surgical care course in Uganda.

BACKGROUND: Low- and middle-income countries like Uganda face a severe shortage of pediatric surgeons. Most children with a surgical emergency are treated by nonspecialist rural providers. We describe the design and implementation of a locally driven, pilot pediatric emergency surgical care course to strengthen skills of these providers. This is the first description of such a course in the current literature. METHODS: The course was delivered three times from 2018 to 2019. Modules include perioperative management, neonatal emergencies, intestinal emergencies, and trauma. A baseline needs assessment survey was administered. Participants in the second and third courses also took pre and postcourse knowledge-based tests. RESULTS: Forty-five providers representing multiple cadres participated. Participants most commonly perform hernia/hydrocele repair (17% adjusted rating) in their current practice and are least comfortable managing cleft lip and palate (mean Likert score 1.4 ±â€¯0.9). Equipment shortage was identified as the most significant challenge to delivering pediatric surgical care (24%). Scores on the knowledge tests improved significantly from pre- (55.4% ±â€¯22.4%) to postcourse (71.9% ±â€¯14.0%, p < 0.0001). CONCLUSION: Nonspecialist clinicians are essential to the pediatric surgical workforce in LMICs. Short, targeted training courses can increase provider knowledge about the management of surgical emergencies. The course has spurred local surgical outreach initiatives. Further implementation studies are needed to evaluate the impact of the training. LEVEL OF EVIDENCE: V.

How We Do It: Creation of a Workforce Development-Focused Track at a Surgical Hackathon.

OBJECTIVE: Healthcare hackathons are fast-paced, mentored events that bring together individuals with diverse skillsets to identify clinical needs and propose solutions. Traditionally geared toward device development and workflow optimization, platforms that address women and minorities in surgery are rare. We aimed to expand the traditional healthcare hackathon model to include a novel workforce development (WD) track to address concerns faced by surgeons and trainees. DESIGN: The WD track was created as part of the first surgical hackathon at our academic institution. In a single-day event, participants identified concerns (pain points) of diversity and sustainability in surgery, formed interdisciplinary teams, and pitched solutions. Pain points, project themes, and postevent survey results were analyzed and compared between WD and other tracks. SETTING: Participants were surveyed at Yale School of Medicine, an academic medical tertiary center, in September 2018. PARTICIPANTS: Thirty-one total participants. Twenty-five (80.6%) responded to the survey. RESULTS: Of 57 problem pitches, 23 (40.4%) were related to WD. Issues highlighted 5 themes: training and career exploration, leadership and communication of skills, mental health and burnout prevention, surgeon discrimination and harassment, and work-life balance. Participants formed 6 groups, with 1 focused on WD. There was no difference between participants in the WD track and non-WD track counterparts with regard to excitement for continuing their project beyond the hackathon (4.00, standard deviation [SD] 0.89, vs. 3.63, SD 1.12, p = 0.43), and in their perception of the mentorship they received (4.00, SD 1.00, vs. 4.11, SD 0.78, p = 0.84). The project presented within the WD track, on culturally sensitive scrub wear, was 1 of 3 prize-winners. CONCLUSIONS: The first WD track at a healthcare hackathon identified 5 themes of unmet workforce needs. The pilot demonstrated that WD tracks can be implemented in hackathons with similar results to traditional tracks and create innovative and sustainable solutions to surgical workforce concerns.

Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina.

Here, we report that the functionality of vascular progenitors (VP) generated from normal and disease-primed conventional human induced pluripotent stem cells (hiPSC) can be significantly improved by reversion to a tankyrase inhibitor-regulated human naïve epiblast-like pluripotent state. Naïve diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve diabetic hiPSC (N-DhiPSC) possessed higher vascular functionality, maintained greater genomic stability, harbored decreased lineage-primed gene expression, and were more efficient in migrating to and re-vascularizing the deep neural layers of the ischemic retina than isogenic diabetic vascular progenitors (DVP). These findings suggest that reprogramming to a stable naïve human pluripotent stem cell state may effectively erase dysfunctional epigenetic donor cell memory or disease-associated aberrations in patient-specific hiPSC. More broadly, tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) represent a class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine.

Correction to: Epidemiology and mortality of pediatric surgical conditions: insights from a tertiary center in Uganda.

In the original publication, the family name of one of the authors was spelt incorrectly. The correct name should read as Nensi Ruzgar.