Implementing stroke care in a lower-middle-income country: results and recommendations based on an implementation study within the Nepal Stroke Project.

Background: Globally, the majority of strokes affect people residing in lower- and lower-middle-income countries (LMICs), but translating evidence-based knowledge into clinical practice in regions with limited healthcare resources remains challenging. As an LMIC in South Asia, stroke care has remained a healthcare problem previously unaddressed at a national scale in Nepal. The Nepal Stroke Project (NSP) aims to improve acute stroke care in the tertiary healthcare sector of Nepal. We hereby describe the methods applied and analyze the barriers and facilitators of the NSP after 18 months. Methods: The NSP follows a four-tier strategy: (1) quality improvement by training healthcare professionals in tertiary care centers; (2) implementation of in-hospital stroke surveillance and quality monitoring system; (3) raising public awareness of strokes; and (4) collaborating with political stakeholders to facilitate public funding for stroke care. We performed a qualitative, iterative analysis of observational data to analyze the output indicators and identify best practices. Results: Both offline and online initiatives were undertaken to address quality improvement and public awareness. More than 1,000 healthcare professionals across nine tertiary care hospitals attended 26 stroke-related workshops conducted by Nepalese and international stroke experts. Monthly webinars were organized, and chat groups were made for better networking and cross-institutional case sharing. Social media-based public awareness campaigns reached more than 3 million individuals. Moreover, live events and other mass media campaigns were instituted. For quality monitoring, the Registry of Stroke Care Quality (RES-Q) was introduced. Collaboration with stakeholders (both national and international) has been initiated. Discussion: We identified six actions that may support the development of tertiary care centers into essential stroke centers in a resource-limited setting. We believe that our experiences will contribute to the body of knowledge on translating evidence into practice in LMICs, although the impact of our results must be verified with process indicators of stroke care.

EMP3 sustains oncogenic EGFR/CDK2 signaling by restricting receptor degradation in glioblastoma.

Epithelial membrane protein 3 (EMP3) is an N-glycosylated tetraspanin with a putative trafficking function. It is highly expressed in isocitrate dehydrogenase-wild-type glioblastoma (IDH-wt GBM), and its high expression correlates with poor survival. However, the exact trafficking role of EMP3 and how it promotes oncogenic signaling in GBM remain unclear. Here, we show that EMP3 promotes EGFR/CDK2 signaling by regulating the trafficking and enhancing the stability of EGFR. BioID2-based proximity labeling revealed that EMP3 interacts with endocytic proteins involved in the vesicular transport of EGFR. EMP3 knockout (KO) enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7 + late endosomes, thereby promoting EGFR degradation. Increased EGFR degradation is rescued by the RAB7 negative regulator and novel EMP3 interactor TBC1D5. Phosphoproteomic and transcriptomic analyses further showed that EMP3 KO converges into the inhibition of the cyclin-dependent kinase CDK2 and the repression of EGFR-dependent and cell cycle transcriptional programs. Phenotypically, EMP3 KO cells exhibit reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to the pan-kinase inhibitor staurosporine and the EGFR inhibitor osimertinib. Furthermore, EGFR-dependent patient-derived glioblastoma stem cells display a transcriptomic signature consistent with reduced CDK2 activity, as well as increased susceptibility to CDK2 inhibition upon EMP3 knockdown. Lastly, using TCGA data, we showed that GBM tumors with high EMP3 expression have increased total and phosphorylated EGFR levels. Collectively, our findings demonstrate a novel EMP3-dependent mechanism by which EGFR/CDK2 activity is sustained in GBM. Consequently, EMP3's stabilizing effect provides an additional layer of tumor cell resistance against targeted kinase inhibition.

Laparoscopic versus robot-assisted Nissen fundoplication in an infant pig model.

PURPOSE: Surgical robots are designed to facilitate dissection and suturing, although objective data on their superiority are lacking. This study compares conventional laparoscopic Nissen fundoplication (CLNF) to robot-assisted Nissen fundoplication (RANF) using computer-based workflow analysis in an infant pig model. METHODS: CLNF and RANF were performed in 12 pigs. Surgical workflow was segmented into phases. Time required to perform specific actions was compared by t test. The quality of knot-tying was evaluated by a skill scoring system. Cardia yield pressure (CYP) was determined to test the efficacy of the fundoplications, and the incidence of complications was compared. RESULTS: There was no difference in average times to complete the various phases, despite faster robotic knot-tying (p = 0.001). Suturing quality was superior in CLNF (p = 0.02). CYP increased similarly in both groups. Workflow-interrupting hemorrhage and pneumothorax occurred more frequently during CLNF (p = 0.040 and 0.044, respectively), while more sutures broke during RANF (p = 0.001). CONCLUSION: The robot provides no clear temporal advantage compared to conventional laparoscopy for fundoplication, although suturing was faster in RANF. Fewer complications were noted using the robot. RANF and CLNF were equally efficient anti-reflux procedures. For robotic surgery to manifest its full potential, more complex operations may have to be evaluated.

Workflow analysis of laparoscopic Nissen fundoplication in infant pigs- a model for surgical feedback and training.

BACKGROUND: Many fields use workflow analysis to assess and improve performance of complex tasks. In pediatric endosurgery, workflow analysis may help optimize operative planning and motor skills by breaking down the procedure into particular phases, evaluating these steps individually, and supplying feedback to the surgeon. OBJECTIVE: To develop a module of computer-based surgical workflow analysis for laparoscopic Nissen fundoplication(LNF) and to evaluate its applicability in an infant pig model. METHODS: LNF was performed in 12 pigs (weight, 7-10 kg) by a single surgeon. Based on synchronized intra and extracorporal movie recordings, the surgical workflow was segmented into temporal operative phases(preparation, dissection, reconstruction and conclusion). During each stage, all actions were recorded in a virtual timeline using a customized workflow editor. Specific tasks, such as knot-tying, were evaluated in detail.Time necessary to perform these actions was compared throughout the study. RESULTS: While time required for the preparation decreased by more than 70% from 4577 to 1379 seconds,and the dissection phase decreased from 2359 to 399 seconds (pig 1 and 12, respectively), the other two phases remained relatively stable. Mean time to perform the entire suture and a 5-throw knot remained constant as well. CONCLUSION: Our workflow analysis model allows the quantitative evaluation of dynamic actions related to LNF.This data can be used to define average benchmark criteria for the procedures that comprise this operation. It thereby permits task-oriented refinement of surgical technique as well as monitoring the efficacy of training.Although preoperative preparation time decreased substantially, and dissection became faster, time required for the reconstruction and conclusion phases remained relatively constant for a surgeon with moderate experience.Likewise, knot-tying did not accelerate in this setting.S-117

Cardia yield pressure measurement in an infant porcine model: a novel technique to evaluate the quality of laparoscopic fundoplication.

BACKGROUND: Cardia yield pressure (CYP) has been described as a measure of the combined effect of all antireflux mechanisms and not simply as another test of lower esophageal sphincter pressure. In this paper, we present a simple technique for the measurement of CYP before and after fundoplication through laparoscopic gastrostomy in an experimental pig model. MATERIALS AND METHODS: Twelve 8-week-old female pigs with a mean weight of 8.7 +/- 0.7 kg underwent laparoscopic gastrostomy placement and Nissen fundoplication under general anesthesia. CYP was determined before and after the fundoplication by filling the stomach with water until reaching the pressure at which the cardia opened and became incompetent. Pre- and postoperative CYP was compared by using the Student's t-test for paired samples. RESULTS: Laparoscopic Nissen fundoplication and gastrostomy was completed in all pigs. CYP increased in all subjects after fundoplication, from a mean of 20 +/- 8 to a mean of 63 +/- 13 cm of H(2)O (p < 0.001). The lowest increase in yield pressure of 17.5 cm was recorded after the first operation. Work-flow analysis revealed that this particular procedure took the longest, that bleeding from the liver was encountered, and shorter sutures than those used on all subsequent fundoplications may have compromised knot tying. CONCLUSIONS: CYP increases consistently after laparoscopic Nissen Fundoplication in young pigs. This parameter may be a good indicator of antireflux efficacy and functional quality of the result. Yield pressure measured through laparoscopic gastrostomy offers a new, feasible, and effective technique for the evaluation of antireflux surgery in an experimental setting. Moreover, this minimally invasive technique may become a simple investigative tool for other antireflux procedures.