The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue--such as the inability to biopsy or test tissue from ...the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy.
Radiology training is an important component of emergency medicine (EM) education, but its delivery has been variable. Program directors have reported a lack of radiology skills in incoming interns. ...A needs assessment is a crucial first step toward improving radiology education among EM residencies. Our objective was to explore the current state of radiology education in EM residency programs.
This was a cross-sectional survey study of all Accreditation Council for Graduate Medical Education-accredited EM programs in the United States. Program leadership completed an online survey consisting of multiple choice, Likert scale, and free-response items. We calculated and reported descriptive statistics.
Of eligible EM programs, 142/252 (56%) completed the survey including 105 postgraduate year (PGY) 1-3 and 36 PGY 1-4 programs. One respondent opted out of answering demographic questions. 23/141 (16%) were from the Western region, 29/141 (21%) were from the North Central region, 14/141 (10%) were from the South-Central region, 28/141 (20%) were from the Southeast region, and 47/141 (33%) were from the Northeast region. A total of 88/142 (62%) of responding programs did not have formal radiology instruction. Of the education that is provided, 127/142 (89%) provide it via didactics/lectures and 115/142 (81%) rely on instruction during clinical shifts. Only 51/142 (36%) provide asynchronous opportunities, and 23/142 (16%) have a dedicated radiology rotation. The majority of respondents reported spending 0-2 hours per month on radiology instruction (108/142; 76%); 95/141 (67%) reported that EM faculty "often" or "always" provide radiology instruction; 134/142 (95%), felt that it was "extremely" or "very important" for ED providers to be able to independently interpret radiograph results; and 129/142 (90.84%) either "sometimes" or "always" rely on their independent radiograph interpretations to make clinical decisions. The radiology studies identified as most important to be able to independently interpret were radiographs obtained for lines/tubes, chest radiographs, and radiographs obtained for musculoskeletal-related complaints.
A minority of EM residency programs have formal instruction in radiology despite the majority of responding program leadership believing that these are important skills. The most important curricular areas were identified. These results may inform the development of formal radiology curricula in EM graduate medical education.
In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a ...unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls.
Safety concerns surrounding the coronavirus 2019 pandemic led to the prohibition of student rotations outside their home institutions. This resulted in emergency medicine (EM)-bound students having ...less specialty experience and exposure to outside programs and practice environments, and fewer opportunities to gain additional Standardized Letters of Evaluation, a cornerstone of the EM residency application. We filled this void by implementing a virtual clerkship.
We created a two-week virtual, fourth-year visiting clerkship focused on advanced medical knowledge topics, social determinants of health, professional development, and professional identity formation. Students completed asynchronous assignments and participated in small group-facilitated didactic sessions. We evaluated the virtual clerkship with pre- and post-medical knowledge tests and evaluative surveys.
We hosted 26 senior medical students over two administrations of the same two-week virtual clerkship. Students had a statistically significant improvement on the medical knowledge post-tests compared to pre-tests (71.7% 21.5/30 to 76.3% 22.9/30). Students reported being exposed to social determinants of health concepts they had not previously been exposed to. Students appreciated the interactive nature of the sessions; networking with other students, residents, and faculty; introduction to novel content regarding social determinants of health; and exposure to future career opportunities. Screen time, technological issues, and mismatch between volume of content and time allotted were identified as potential challenges and areas for improvement.
We demonstrate that a virtual EM visiting clerkship is feasible to implement, supports knowledge acquisition, and is perceived as valuable by participants. The benefits seen and challenges faced in the development and implementation of our clerkship can serve to inform future virtual clerkships, which we feel is a complement to traditional visiting clerkships even though in-person clerkships have been re-established.
Professional development is an important component of graduate medical education, but it is unclear how to best deliver this instruction. Book clubs have been used outside of medicine as a ...professional development tool. We sought to create and evaluate a virtual professional development book club for emergency medicine interns.
We designed and implemented a virtual professional development book club during intern orientation. Afterward, participants completed an evaluative survey consisting of Likert and free-response items. Descriptive statistics were reported. We analyzed free-response data using a thematic approach.
Of 15 interns who participated in the book club, 12 (80%) completed the evaluative survey. Most (10/12; 83.3%) agreed or strongly agreed that the book club showed them the importance of professional development as a component of residency training and helped them reflect on their own professional (11/12; 91.7%) and personal development (11/12; 91.7%). Participants felt the book club contributed to bonding with their peers (9/12; 75%) and engagement with the residency program (9/12; 75%). Our qualitative analysis revealed five major themes regarding how the book club contributed to professional and personal development: alignment with developmental stage; deliberate practice; self-reflection; strategies to address challenges; and communication skills.
A virtual book club was feasible to implement. Participants identified multiple ways the book club positively contributed to their professional development. These results may inform the development of other book clubs in graduate medical education.
Recent advances in sample preparation and analysis for next generation sequencing have made it possible to profile and discover new miRNAs in a high throughput manner. In the case of neurological ...disease and injury, these types of experiments have been more limited. Possibly because tissues such as the brain and spinal cord are inaccessible for direct sampling in living patients, and indirect sampling of blood and cerebrospinal fluid are affected by low amounts of RNA. We used a mouse model to examine changes in miRNA expression in response to acute nerve crush. We assayed miRNA from both muscle tissue and blood plasma. We examined how the depth of coverage (the number of mapped reads) changed the number of detectable miRNAs in each sample type. We also found that samples with very low starting amounts of RNA (mouse plasma) made high depth of mature miRNA coverage more difficult to obtain. Each tissue must be assessed independently for the depth of coverage required to adequately power detection of differential expression, weighed against the cost of sequencing that sample to the adequate depth. We explored the changes in total mapped reads and differential expression results generated by three different software packages: miRDeep2, miRNAKey, and miRExpress and two different analysis packages, DESeq and EdgeR. We also examine the accuracy of using miRDeep2 to predict novel miRNAs and subsequently detect them in the samples using qRT-PCR.
In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E ...(APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk.
►The GAB2 gene was implicated in the first genome-wide association study of AD. ►FDG PET can be used as a presymptomatic endophenotype to assess AD risk factors. ►APOEe4 carriers with a protective GAB2 haplotype had higher FDG uptake in AD areas. ►The GAB2 haplotype may reduce the risk of AD in APOEe4 carriers.
Numerical evaluations of Feynman integrals
often proceed via a deformation of the integration contour into the complex plane. While valid contours are easy to construct, the numerical precision for a ...multi-loop integral can depend critically on the chosen contour. We present methods to optimize this contour using a combination of optimized, global complex shifts and a normalizing flow. They can lead to a significant gain in precision.
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