关键词： Uveal melanoma   Alternative splicing   Prognostic model   Bioinformatic analysis  

摘要： As a posttranscriptional regulatory mechanism, alternative splicing (AS) has the potential to generate a large amount of protein diversity from limited genes. The purpose of our study was to assess the usefulness of prognostic splicing events as novel diagnostic and therapeutic signatures for uveal melanoma (UM). The datasets, clinical traits and AS data of UM were obtained from The Cancer Genome Atlas (TCGA) database and TCGA SpliceSeq database. Using bioinformatics analysis, we identified 1047 AS events as candidate AS events closely related to prognosis from 920 parent genes. The gene enrichment analysis indicated that these genes were mainly enriched in cellular components (CC) including cytosol, nucleoplasm, cytoplasm and ribosome, and in molecular functions (MF), including protein binding and poly(A) RNA binding. Furthermore, we selected all survivalassociated splicing events to generate prognostic signatures, which included 4 exon skip (ES) events (DNASE1L1-90581-ES, NUDT1-78611-ES, BIN1-55198-ES, SEPN1-1195-ES) and 1 alternate promoter (AP) event (DPYSL2-83132-AP). The AS prognostic model was confirmed as independent overall survival (OS)-related factors (p = 0.014). A total of 17 splicing factors (SFs) involved in the regulation of AS were identified as related to the OS of UM patients. Our pooled data highlighted the usefulness and importance of AS biomarkers, which provided a potential strategy for the diagnosis and treatment of UM.

摘要： Public health concerns related to the COVID-19 pandemic are leading many residency and fellowship programs to transition from in-person to videoconference interviews (VCIs). The magnitude and speed of the shift to VCIs, the lack of existing research around bias and VCIs, and the underlying stress on all involved related to the pandemic put programs at risk of implementing virtual interviews without fully exploring their implications for diversity and equity. VCIs can promote diversity efforts by reducing the need for travel, making interviews more convenient and cost effective for applicants. However, VCIs may also introduce new biases and amplify existing biases in recruitment. VCIs introduce a dependence on technology to conduct the interview process, which may amplify systemic inequities in access to broadband internet and high-quality hardware. Communication delays due to technology challenges may negatively affect interview scores. Additionally, users experience increased cognitive load when participating in videoconferences, which can activate implicit biases. Exposure to cues in the interviewee's personal living situation previously unavailable to interviewers may lead to unconscious assumptions by interviewers, which may also influence scoring. Graduate medical education programs committed to maintaining equitable recruitment processes must be able to recognize potential biases in VCIs and implement strategies to mitigate them. This article identifies some of the biases VCIs can introduce to the recruitment process and offers strategies for programs to mitigate them. These include making interviewers aware of potential technology-based inequities, encouraging interviewers to minimize multitasking, and offering guidance on use of standardized backgrounds. The authors also recognize the limitations of offering behavioral strategies to mitigate systemic inequities and suggest that structural changes are needed to ensure equitable access to technology.

摘要： Objective Low- and middle-income countries account for over 90% of all road traffic injury deaths. Despite this, formal training in trauma management is not widely adopted in these countries. No specific training was available in prehospital or emergency department for life support before primary trauma care (PTC) course. This study was conducted to assess the effectiveness of the PTC course in the improvement of knowledge and skills of trauma management among participant in Pakistan. Method Two days of PTC courses were organised and conducted in various regions of Pakistan, participants per course comprising medical students, doctors, house officers, residents, and paramedics. The course comprises lectures of 5 hours and 30 minutes, skills workshops for 3 hours and discussion and multisystem trauma scenarios for 3 hours. Trauma management knowledge and clinical confidence of candidates were assessed using a predetermined multiple-choice questionnaire of 30 MCQs both at pre- and post-course, and using clinical scenarios, confidence matrix was assessed. Results A total 7852 of participants were trained, an average of 2 courses per month and 302 total courses. Mean score of pre-course MCQs was 60% and mean score of post-course MCQs was 82%. Among the participant postgraduate trainees, average in trauma knowledge and trauma clinical confidence were significantly higher in both pre- and post-course. The mean score of pre-course confidence matrix was 70% and the mean score of post-course confidence matrix was 93%;at the end of course, all participants showed a high level of confidence in managing trauma mock scenarios. A total of 5889 (75%) participants had a >= 78.5% post-workshop knowledge score. However, only 1963 (25%) participants had a trauma skill score with <= 75 marks. Conclusion PTC workshop could be an alternative and cost-effective flexible course for gaining knowledge and clinical skills of initial trauma management and strengthening the capacity of trauma m

关键词： Travel satisfaction   Travel captivity   Mode choice   Travel behavior  

摘要： In this study, we investigated travel captivity from the perspective of travel satisfaction. Using survey data from 565 commuters in Portland, Oregon, we compared satisfaction with the most recent commute trip (using the chosen mode) and hypothetical commute satisfaction if using an alternative mode. The difference in travel satisfaction between the chosen and alternative mode - referred to as the travel satisfaction gap - was used as a fine-grained proxy measure of travel captivity. Results indicate that active mode (walk/bicycle) users would be less satisfied when the alternative modes were auto or transit, while auto and transit commuters would be slightly more satisfied if they commuted by walking or bicycling. These outcomes suggest that auto users are most captive, while active travelers are mostly choice users. Results also show that respondents would be more satisfied with an alternative mode if it would enable more talking to other passengers.

摘要： BACKGROUND Successful airway management is a priority in the resuscitation of critically ill or traumatised patients. Several studies have demonstrated the importance of achieving maximum first pass success, particularly in prehospital advanced airway management. OBJECTIVE To compare success rates of emergency intubations between patients requiring cardiopulmonary resuscitation (CPR) for cardiac arrest (CPR group) and other emergencies (non-CPR group) using the C-MAC PM videolaryngoscope. DESIGN Ongoing analysis of prospective collected prehospital advanced airway management core variables. SETTING Single helicopter emergency medical service (HEMS) 'Christoph 22', Ulm Military Hospital, Germany, May 2009 to July 2018. PATIENTS We included all 1006 HEMS patients on whom prehospital advanced airway management was performed by board-certified anaesthesiologists on call at HEMS 'Christoph 22'. INTERVENTIONS The C-MAC PM was used as the first-line device. The initial direct laryngoscopy was carried out using the C-MAC PM without the monitor in sight. After scoring the direct laryngoscopic view according to the Cormack and Lehane grade, the monitor was folded within the sight of the physician and tracheal intubation was performed using the videolaryngoscopic view without removing the blade. MAIN OUTCOME MEASURES The primary outcome was successful airway management. Secondary outcomes were the patient's position during airway management, necessity for suction, direct and videolaryngoscopic view according to Cormack and Lehane grading, as well as number of attempts needed for successful intubation. RESULTS A patent airway was achieved in all patients including rescue techniques. There was a lower first pass success rate in the CPR group compared with the non-CPR group (84.4 vs. 91.4%, P = 0.01). In the CPR group, direct laryngoscopy resulted more often in a clinically unfavourable (Cormack and Lehane grade 3 or 4) glottic view (CPR vs. non-CPR-group 37.2 vs. 26.7%, P = 0.00

摘要： Calls for curricular reform in medical schools and enhanced integration of basic and clinical science have resulted in a shift toward preclerkship curricula that enhance the clinical relevance of foundational science instruction and provide students with earlier immersion in the clinical environment. These reforms have resulted in shortened preclerkship curricula, yet the promise of integrated basic science education into clerkships has not been sufficiently realized because of barriers such as the nature of clinical practice, time constraints, and limited faculty knowledge. As personalized medicine requires that physicians have a more nuanced understanding of basic science, this is cause for alarm. To address this problem, several schools have developed instructional and assessment strategies to better integrate basic science into the clinical curriculum. In this article, faculty and deans from 11 U.S. medical schools discuss the strategies they implemented and the lessons they learned to provide guidance to other schools seeking to enhance basic science education during clerkships. The strategies include program-level interventions (e.g., longitudinal sessions dedicated to basic science during clerkships, weeks of lessons dedicated to basic science interspersed in clerkships), clerkship-level interventions (e.g., case-based learning with online modules, multidisciplinary clerkship dedicated to applied science), bedside-level interventions (e.g., basic science teaching scripts, self-directed learning), and changes to formative and summative assessments (e.g., spaced repetition/leveraging test-enhanced learning, developing customized examinations). The authors discovered that: interventions were more successful when buy-in from faculty and students was considered, central oversight by curricular committees collaborating with faculty was key, and some integration efforts may require schools to provide significant resources. All schools administered the United States

关键词： alternative promoters   cancer   epigenetics   glioma   glioma stem cells   HOX genes  

摘要： In human, the 39 coding HOX genes and 18 referenced noncoding antisense transcripts are arranged in four genomic clusters named HOXA, B, C, and D. This highly conserved family belongs to the homeobox class of genes that encode transcription factors required for normal development. Therefore, HOX gene deregulation might contribute to the development of many cancer types. Here, we study HOX gene deregulation in adult glioma, a common type of primary brain tumor. We performed extensive molecular analysis of tumor samples, classified according to their isocitrate dehydrogenase (IDH1) gene mutation status, and of glioma stem cells. We found widespread expression of sense and antisense HOX transcripts only in aggressive (IDHwt) glioma samples, although the four HOX clusters displayed DNA hypermethylation. Integrative analysis of expression, DNA methylation, and histone modification signatures along the clusters revealed that HOX gene upregulation relies on canonical and alternative bivalent CpG island promoters that escape hypermethylation. H3K27me3 loss at these promoters emerges as the main cause of widespread HOX gene upregulation in IDHwt glioma cell lines and tumors. Our study provides the first comprehensive description of the epigenetic changes at HOX clusters and their contribution to the transcriptional changes observed in adult glioma. It also identified putative 'master' HOX proteins that might contribute to the tumorigenic potential of glioma stem cells.

关键词： breast cancer   dosing   HER2   modeling   pertuzumab   population pharmacokinetics  

摘要： PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab is currently approved with an initial loading dose of 840 mg, followed by a 420-mg maintenance dose intravenously every 3 weeks. A reloading dose is required if there is a >= 6-week delay in treatment. In response to the potential treatment disruption due to COVID-19, the impact of dose delays and alternative dosing regimens on intravenous pertuzumab for human epidermal growth factor receptor 2-positive breast cancer treatment is presented. Simulations were conducted by using the validated population pharmacokinetic model for pertuzumab, and included (1) 4-, 6-, and 9-week dose delays of the 840 mg/420 mg every 3 weeks dosing regimen and (2) 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens. Simulations were compared with the currently approved pertuzumab dosing regimen. The simulations in 1000 virtual patients showed that a dose reload (840 mg) is required following a dose delay of >= 6 weeks to maintain comparable C-trough (lowest concentration before the next dose is given) levels to clinical trials. The 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens decrease median steady-state C-trough by approximate to 40% compared with the approved regimen, and <90% of patients will be above the target C-trough. Thus, the alternative 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks pertuzumab dosing regimens are not recommended. Flexibility for intravenous PERJETA-based regimens is available with an alternative route of pertuzumab administration (subcutaneous vs intravenous).

关键词： Karst rocky desertification   Rural energy   Biomass energy   Southwestern China  

摘要： Karst in southwestern China forms a rocky desertification area with a particularly vulnerable ecological environment. Studying the potential of agricultural available biomass energy in this region is of great significance for the construction of the rural energy industry and ecological environment protection in karst mountains. This study investigated three regions with different degrees of rocky desertification in the karst mountains of southwestern China. The characteristics of rural energy consumption and their impact on the ecology of Karst region were analyzed. Moreover, the total available agricultural biomass energy resources in the study area were estimated via residue to product ratio, ecological returning coefficient, collection coefficient, conversion coefficient, and by-product coefficient. The research results indicate that the fragile karst ecological environment and the over-consumption of fuelwood resources are the most important reasons for the evolution of rocky desertification in this region, which exposes karst rocky desertification areas and increases the risk of rocky desertification. Given abundant agricultural biomass energy reserves in karst regions of southwestern China, promoting biomass energy as an alternative for fuelwood carries great significance for ecological protection of karst regions. This can serve as an important measure to promote ecological restoration in karst rocky desertification areas.