Optimal content for a surgical curriculum for general practice in Rwanda: A Delphi study.

BACKGROUND: In Rwanda, a nationwide shortage of surgeons necessitates general practitioners (GPs) perform many common procedures and minor surgeries. However, GPs only receive a 1-year internship to prepare them to provide this care. We performed a Delphi survey of practicing GPs to assess essential content for a surgical curriculum for Rwandan interns to better prepare them for general practice. METHODS: We invited 56 practicing GPs to participate in a two-round anonymous electronic survey in February 2023. The first round assessed demographics and solicited free-text responses to gather knowledge and procedural content suggestions for the curriculum. The second round refined these responses into key content areas. RESULTS: Thirty-one GPs responded to both rounds of the Delphi survey. They provided insight into the most commonly performed procedures, most important technical skills, and the top areas of surgical knowledge necessary for general practice. They expressed a need for more exposure to a variety of surgical pathologies and interventions across multiple specialties, highlighting the value of foundational skills in trauma, obstetrics and gynecology, and orthopedics, both at the beginning of their internship, as well as at the beginning of their general practice. CONCLUSIONS: GPs emphasized the importance of broad exposure to common acute surgical pathology and interventions across several surgical subspecialties, as well as a need for foundational technical skills and surgical knowledge. The results of our study underscore the necessity of a surgical education providing a solid basis in the foundational knowledge and techniques of surgical care.

Identification of a combined hypoxia and lactate metabolism prognostic signature in lung adenocarcinoma : Author.

BACKGROUND: In the tumor microenvironment (TME), a bidirectional relationship exists between hypoxia and lactate metabolism, with each component exerting a reciprocal influence on the other, forming an inextricable link. The aim of the present investigation was to develop a prognostic model by amalgamating genes associated with hypoxia and lactate metabolism. This model is intended to serve as a tool for predicting patient outcomes, including survival rates, the status of the immune microenvironment, and responsiveness to therapy in patients with lung adenocarcinoma (LUAD). METHODS: Transcriptomic sequencing data and patient clinical information specific to LUAD were obtained from comprehensive repositories of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A compendium of genes implicated in hypoxia and lactate metabolism was assembled from an array of accessible datasets. Univariate and multivariate Cox regression analyses were employed. Additional investigative procedures, including tumor mutational load (TMB), microsatellite instability (MSI), functional enrichment assessments and the ESTIMATE, CIBERSORT, and TIDE algorithms, were used to evaluate drug sensitivity and predict the efficacy of immune-based therapies. RESULTS: A novel prognostic signature comprising five lactate and hypoxia-related genes (LHRGs), PKFP, SLC2A1, BCAN, CDKN3, and ANLN, was established. This model demonstrated that LUAD patients with elevated LHRG-related risk scores exhibited significantly reduced survival rates. Both univariate and multivariate Cox analyses confirmed that the risk score was a robust prognostic indicator of overall survival. Immunophenotyping revealed increased infiltration of memory CD4 + T cells, dendritic cells and NK cells in patients classified within the high-risk category compared to their low-risk counterparts. Higher probability of mutations in lung adenocarcinoma driver genes in high-risk groups, and the MSI was associated with the risk-score. Functional enrichment analyses indicated a predominance of cell cycle-related pathways in the high-risk group, whereas metabolic pathways were more prevalent in the low-risk group. Moreover, drug sensitivity analyses revealed increased sensitivity to a variety of drugs in the high-risk group, especially inhibitors of the PI3K-AKT, EGFR, and ELK pathways. CONCLUSIONS: This prognostic model integrates lactate metabolism and hypoxia parameters, offering predictive insights regarding survival, immune cell infiltration and functionality, as well as therapeutic responsiveness in LUAD patients. This model may facilitate personalized treatment strategies, tailoring interventions to the unique molecular profile of each patient's disease.

Reproductive health among women of child-bearing age after surgery for Rheumatic Heart Disease in Rwanda.

OBJECTIVE: To determine maternal and fetal outcomes in postoperative women with RHD who become pregnant after valve surgery and evaluate current anticoagulation management during pregnancy. METHODS: Data from the Rwandan RHD cardiac surgical registry identified all female patients who underwent valve surgery before or during childbearing age since 2006. 136 participants completed a mixed-methods questionnaire detailing each pregnancy after surgery, including anticoagulation regimen and outcomes. RESULTS: 38.2% (n=136) of patients reported at least one pregnancy after surgery, of which more than half were unintentional (53.9%, n=52). Among those with mechanical valves, most remained on warfarin alone during pregnancy (58.5%, n=53) while one third were switched to low molecular weight heparin during the first, second, or third trimesters (5 vs. 4 vs. 7, n=18). Women with bioprosthetic valve replacement or valve repair were more likely to experience live term births (84.6% vs 45.3%, p<0.01) and less likely to report spontaneous abortion (3.9% vs 30.2%, p<0.01) compared to women with mechanical valve replacement. Excessive bleeding was the most common complication during pregnancy (9.1%, n=79), and two infants were diagnosed with congenital defects associated with warfarin embryopathy (4.8%, n=42). CONCLUSIONS: Despite preoperative counseling discouraging conception, many women with prosthetic valves still become pregnant after surgery. The results of this study will inform evidence-based and context-specific practices for anticoagulation during pregnancy in Rwanda and the region.

Uncommon presentations of type A quadricuspid aortic valve in the Septuagenarian.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital anomaly characterized by the presence of four cusps instead of the usual three. It is estimated to occur in less than 0.05% of the population, with Type A (four equal-sized leaflets) accounting for roughly 30% of QAV subtypes. Based on limited clinical series, the usual presentation is progressive aortic valve regurgitation (AR) with symptoms occurring in the fourth to sixth decade of life. Severe aortic valve stenosis (AS) and acute AR are very uncommon. CASE PRESENTATION: We describe two cases of Type A QAV in patients who remained asymptomatic until their seventies with very uncommon presentations: one with severe AS and one with acute, severe AR and flail leaflet. In Case A, a 72-year-old patient with history of moderate AS presents to clinic with progressive exertional dyspnea. During work-up for transcatheter vs. surgical replacement pre-operative computed tomography angiogram (CTA) reveals a quadricuspid aortic valve with severe AS, and the patient undergoes surgical aortic valve replacement. Pre-discharge transthoracic echocardiography (TTE) shows good prosthetic valve function with no gradient or regurgitation. In Case B, a 76-year-old patient is intubated upon arrival to the hospital for acute desaturation, found to have wide open AR on catheterization, and transferred for emergent intervention. Intraoperative TEE reveals QAV with flail leaflet and severe AR. Repair is considered but deferred ultimately due to emergent nature. Post-operative TTE demonstrates good prosthetic valve function with no regurgitation and normal biventricular function. CONCLUSIONS: QAV can present as progressive severe AS and acute AR, with symptoms first occurring in the seventh decade of life. The optimal treatment for QAV remains uncertain. Although aortic valve repair or transcatheter option may be feasible in some patients, aortic valve replacement remains a tenable option.

Recent advances in c-Met-based dual inhibitors in the treatment of cancers.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

Deciphering a global source of non-genetic heterogeneity in cancer cells.

Cell-to-cell variability within a clonal population, also known as non-genetic heterogeneity, has created significant challenges for intervening with diseases such as cancer. While non-genetic heterogeneity can arise from the variability in the expression of specific genes, it remains largely unclear whether and how clonal cells could be heterogeneous in the expression of the entire transcriptome. Here, we showed that gene transcriptional activity is globally modulated in individual cancer cells, leading to non-genetic heterogeneity in the global transcription rate. Such heterogeneity contributes to cell-to-cell variability in transcriptome size and displays both dynamic and static characteristics, with the global transcription rate temporally modulated in a cell-cycle-coupled manner and the time-averaged rate being distinct between cells and heritable across generations. Additional evidence indicated the role of ATP metabolism in this heterogeneity, and suggested its implication in intrinsic cancer drug tolerance. Collectively, our work shed light on the mode, mechanism, and implication of a global but often hidden source of non-genetic heterogeneity.

Developing a Surgical Simulation Curriculum for the Rwandan Context.

OBJECTIVE: We report on the development and implementation of a surgical simulation curriculum for undergraduate medical students in rural Rwanda. DESIGN: This is a narrative report on the development of scenario and procedure-based content for a junior surgical clerkship simulation curriculum by an interdisciplinary team of simulation specialists, surgeons, anesthesiologists, medical educators, and medical students. SETTING: University of Global Health Equity, a new medical school located in Butaro, Rwanda. PARTICIPANTS: Participants in this study consist of simulation and surgical educators, surgeons, anesthesiologists, research fellows and University of Global Health Equity medical students enrolled in the junior surgery clerkship. RESULTS: The simulation training schedule was designed to begin with a 17-session simulation-intensive week, followed by 8 sessions spread over the 11-week clerkship. These sessions combined the use of high-fidelity mannequins with improvised, bench-top surgical simulators like the GlobalSurgBox, and low-cost gelatin-based models to effectively replace resource intensive options. CONCLUSIONS: Emphasis on contextualized content generation, low-cost application, and interdisciplinary design of simulation curricula for low-income settings is essential. The impact of this curriculum on students' knowledge and skill acquisition is being assessed in an ongoing fashion as a substrate for iterative improvement.

Development and validation of a diagnostic model for AFP-negative hepatocellular carcinoma.

PURPOSE: AFP appears to be negative in about 30% of overall hepatocellular carcinoma (HCC). Our study aimed to develop a nomogram model to diagnose AFP-negative HCC (AFPN-HCC). PATIENTS AND METHODS: The training set included 294 AFPN-HCC patients, 159 healthy objects, 63 patients with chronic hepatitis B(CHB), and 64 patients with liver cirrhosis (LC). And the validation set enrolled 137 healthy controls objects, 47 CHB patients and 45 patients with LC. LASSO, univariate, and multivariable logistic regression analysis were performed to construct the model and then transformed into a visualized nomogram. The receiver operating characteristic (ROC) curves, the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were further used for validation. RESULTS: Four variables including age, PIVKA-II, platelet (PLT) counts, and prothrombin time (PT) were selected to establish the nomogram. The area under the curve (AUC) of the ROC to distinguish AFPN-HCC patients was 0.937(95% CI 0.892-0.938) in training set and 0.942(95% CI 0.921-0.963) in validation set. We also found that the model had high diagnostic value for small-size HCC (tumor size < 5 cm) (AUC = 0.886) and HBV surface antigen-positive AFPN-HCC (AUC = 0.883). CONCLUSIONS: Our model was effective for discrimination of AFPN-HCC from patients with benign liver diseases and healthy controls, and might be helpful for the diagnosis for AFPN-HCC.

Long-Term Patient-Reported Symptom Improvement and Quality of Life after Transthoracic Diaphragm Plication in Adults.

BACKGROUND: Open and robotic-assisted transthoracic approaches for diaphragm plication are accepted surgical interventions for diaphragm paralysis and eventration. However, long-term patient-reported symptom improvement and quality of life (QOL) remains unclear. STUDY DESIGN: A telephone-based survey was developed focusing on postoperative symptom improvement and QOL. Patients who underwent open or robotic-assisted transthoracic diaphragm plication (2008-2020) across three institutions were invited to participate. Patients who responded and provided consent were surveyed. Likert responses on symptom severity were dichotomized and rates before and after surgery were compared using McNemar's test. RESULTS: Forty-one percent of patients participated (43 of 105 responded, mean age 61.0 years, 67.4% male, 37.2% robotic-assisted surgery), with an average time between surgery and survey of 4.1 ± 3.2 years. Patients reported significant improvement in dyspnea while lying flat (67.4% pre- vs 27.9% postoperative, p < 0.001), dyspnea at rest (55.8% pre- vs 11.6% postoperative, p < 0.001), dyspnea with activity (90.7% pre- vs 55.8% postoperative, p < 0.001), dyspnea while bending over (79.1% pre- vs 34.9% postoperative, p < 0.001), and fatigue (67.4% pre- vs 41.9% postoperative, p = 0.008). There was no statistical improvement in chronic cough. 86% of patients reported improved overall QOL, 79% had increased exercise capacity, and 86% would recommend surgery to a friend with a similar problem. Analysis comparing open and robotic-assisted approaches found no statistically significant differences in symptom improvement or QOL responses between the groups. CONCLUSIONS: Patients report significantly improved dyspneic and fatigue symptoms after transthoracic diaphragm plication, regardless of open or robotic-assisted approach. The majority of patients report improved QOL and exercise capacity.

GlobalSurgBox: A Portable Surgical Simulator for Surgical Trainees Worldwide.

OBJECTIVES: Identify barriers to surgical simulation in multiple countries across the income spectrum. Evaluate whether a novel, portable surgical simulator (GlobalSurgBox) would be valuable to surgical trainees and overcome these barriers. DESIGN: Trainees from high-, middle-, and low-income countries were instructed on how to perform surgical skills using the GlobalSurgBox. Participants were sent an anonymized survey after 1 week to evaluate practicality and helpfulness of the trainer. SETTING: Academic medical centers in 3 countries: USA, Kenya, and Rwanda. PARTICIPANTS: 48 medical students, 48 surgery residents, 3 medical officers, and 3 cardiothoracic surgery fellows. RESULTS: 99.0% of respondents agreed surgical simulation was an important aspect of surgical education. Despite 60.8% having access to simulation resources, only 3 of 40 (7.5%) US trainees, 2 of 12 (16.7%) of Kenyan trainees, and 1 of 10 (10.0%) Rwandan trainees used these resources routinely. 38 (95.0%) US trainees, 9 (75.0%) Kenyan trainees, and 8 (80.0%) Rwandan trainees with access to simulation resources stated there were barriers to using them. The frequently cited barriers included lack of convenient access and lack of time. After using the GlobalSurgBox, 5 (7.8%) US participants, 0 (0%) Kenyan participants, and 5 (38.5%) Rwandan participants reported lack of convenient access as a continued barrier to simulation. 52 (81.3%) US trainees, 24 (96.0%) Kenyan trainees, and 12 (92.3%) Rwandan trainees stated the GlobalSurgBox was a good facsimile of the operating room. 59 (92.2%) US trainees, 24 (96.0%) Kenyan trainees, and 13 (100%) Rwandan trainees stated the GlobalSurgBox better prepared them for clinical settings. CONCLUSIONS: A majority of trainees across all 3 countries reported multiple barriers to simulation in their current surgical training. The GlobalSurgBox eliminates many of these barriers by providing a portable, affordable, and realistic way to practice skills needed in the operating room.

Global cardiothoracic surgery: A survey of trainees' interests and barriers.

Background: More than 5 billion people lack access to surgical care, disproportionately in low- and middle-income countries. The emerging literature demonstrates high interest in global surgery across specialties; however, participation in global cardiothoracic surgical care remains low. To date, there has been no research quantifying the attitudes of cardiothoracic surgeons about global surgery. Our study aimed to acquire a broader understanding of cardiothoracic surgical trainees' interest in global surgery to address barriers and promote cardiac healthcare worldwide. Methods: An online survey was sent to all North American cardiothoracic surgical residents via the Thoracic Surgery Residents Association email listserv. The survey was designed in the REDCap database and administered twice, in 2021 and 2022. Data were analyzed by descriptive and chi-square analysis using Stata. Results: Seventy-three cardiothoracic surgical trainees responded to our survey, of whom 95.3% considered increasing cardiothoracic surgical access to be important, and 67.2% identified this as a future career priority. Most respondents (82.8%) would participate in global surgery if opportunities were available through their home institution. Lack of opportunities (70.0%) and finances (66.7%) were the primary barriers to participation. Respondents identified funding (85%) and institutional support (83.3%) as the most significant incentives to increase involvement. Conclusions: There is strong interest in global surgery among cardiothoracic trainees; however, involvement remains low. A consensus among the North American cardiothoracic surgical community is needed to address barriers to global volunteerism within surgical residency and improve access to cardiac surgery worldwide.

Glucose-independent insulin and glucagon secreted from ventral pancreas sharing a similar pattern in healthy adult rat.

Elevated blood glucose concentration due to food intake will trigger insulin secretion from the dorsal pancreas has been extensively studied. This increased intracellular insulin level can stimulate glucagon release from intra-islets. However, the interaction between glucagon and insulin under a fasting state is unknown. To explore the relationship, we partially removed the ventral and dorsal pancreas on wild-type adult rats. The glucose tolerance test was conducted to measure influence of the surgery on the integrity function of the pancreas. The fasting insulin/glucagon level before and after surgery were measured by the ELISA kit. The statistical analyses indicated that the ventral removal of the pancreas had higher fasting glucose than that of dorsal removal. And only the ventral removal group showed significantly increased basal insulin and basal glucagon levels. Our findings showed differential role of the ventral pancreas in response to a glucose-free stimulus and also provided the possible in vitro target for developing the anti-hyperglycemic drugs.

Development of a Modular and Equitable Surgical Simulator.

There is a tremendous need for affordable and accessible surgical simulators in the United States and abroad. Our group developed a portable, modular, inexpensive surgical simulator designed for all levels of surgical trainees, from medical students to cardiothoracic surgery fellows, and adaptable to a variety of surgical specialties. Our goal is to provide a platform for innovative surgery simulation that applies to any learner or resource setting. We describe the development, assembly, and future directions for this simulator.

Minimally Invasive Thoracic Surgery for Low- and Middle-Income Countries.

The burden of respiratory and upper-gastrointestinal diseases especially affects low- and middle-income countries. Five billion people lack access to safe, timely, and affordable surgical care, including thoracic surgical care. Minimally invasive thoracic surgery (MITS) has been shown to reduce complications, shorten hospital lengths of stay, and minimize health care costs, thereby enabling patients to pay less out-of-pocket and/or limit time away from work and families. Experiences with MITS exist but are limited in low- and middle-income countries; professional societies, academic institutions, policymakers, and industry can facilitate scale-up of MITS by increasing financing, expanding surgical training, and optimizing surgical supply chains.

Proteomic Mapping and Targeting of Mitotic Pericentriolar Material in Tumors Bearing Centrosome Amplification.

Recent work has made it clear that pericentriolar material (PCM), the matrix of proteins surrounding centrioles, contributes to most functions of centrosomes. Given the occurrence of centrosome amplification in most solid tumors and the unconventional survival of these tumor cells, it is tempting to hypothesize that gel-like mitotic PCM would cluster extra centrosomes to defend against mitotic errors and increase tumor cell survival. However, because PCM lacks an encompassing membrane, is highly dynamic, and is physically connected to centrioles, few methods can decode the components of this microscale matrix. In this study, we took advantage of differential labeling between two sets of APEX2-centrosome reactions to design a strategy for acquiring the PCM proteome in living undisturbed cells without synchronization treatment, which identified 392 PCM proteins. Localization of ubiquitination promotion proteins away from PCM was a predominant mechanism to maintain the large size of PCM for centrosome clustering during mitosis in cancer cells. Depletion of PCM gene kinesin family member 20A (KIF20A) caused centrosome clustering failure and apoptosis in cancer cells in vitro and in vivo. Thus, our study suggests a strategy for targeting a wide range of tumors exhibiting centrosome amplification and provides a proteomic resource for future mining of PCM proteins. SIGNIFICANCE: This study identifies the proteome of pericentriolar material and reveals therapeutic vulnerabilities in tumors bearing centrosome amplification.