Citations

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Objective The goal of this study was to determine the effectiveness of a video presentation to first‐year medical students in clarifying their professional roles in the anatomy laboratory. Methods At the Mayo Clinic in 2005, we created a 10‐minute video interview of a woman whose parents donated their bodies to the anatomy program. In the interview, she discussed the lives of her parents, their message for medical students, and medical students’ roles in professionalism and confidentiality. First‐year anatomy students viewed the video during the first week of their anatomy course and were surveyed using an 11‐point Likert scale to assess the impact of the video (0=strongly disagree, 10=strongly agree). Results Students generally agreed that the video helped them understand professionalism and, especially, confidentiality in the context of the gross anatomy laboratory. Students tended to agree, although slightly less strongly, that they gained a deeper respect for donors after watching the video. Many believed that potential donors would benefit from viewing the video presentation. Finally, most students strongly agreed that future medical students would benefit from watching the video interview. Conclusions The results support the hypothesis that the video presentation clarifies medical students’ professional roles in protecting the confidentiality and humanity of the donors. Students generally agreed that it is worth showing to future classes of medical students. Furthermore, the video may benefit those contemplating body donation.

The Department of Anatomy at Mayo Clinic, Rochester, MN serves medical students, allied health profession students, residents, fellows, Mayo Clinic consultants and partners with Mayo School of Continuing Medical Education with an opportunity to learn anatomy and to practice surgical procedures and approaches, to develop and improve new techniques on unembalmed fresh tissue. The Procedural Skills Laboratory's (PSL) flexible design allows diverse usage of lab space for multiple small groups as well as large groups of up to 100 participants. The PSL provides an opportunity for residency directors to incorporate surgical and procedural training in a "safe" environment from which learners can advance from traditional "passive" learning to active participation in complicated surgical procedures. An example of such activities include courses in arthroscopic and laparoscopic procedures, pelvic and thoracic dissection utilizing Da Vinci surgical robot, central line placement, airway management, and many others. This hands on active training provides all lab participants with an opportunity to acquire knowledge, skills and competencies which directly translate to increased quality of patient care.

Objective The objective of this study was to introduce musculoskeletal physical examination skills in the gross anatomy course as a teaching tool and to evaluate medical students’ perceptions of this experience. Methods A list of 27 clinical examinations of the upper and lower limbs was generated from published core recommendations for undergraduate medical education. During gross anatomy laboratory sessions, teaching assistants (third year medical students) presented one or two of the clinical skills related to that day’s dissection to groups of 3–4 students at a time. The anatomic relationships tested by the clinical examinations were highlighted. One question on the laboratory examination at the end of the unit was an Objective Structured Clinical Examination (OSCE) station where students were given a clinical scenario and asked to demonstrate a physical examination that they would use in evaluating the patient. Following the upper and lower limb units, the students were given a Likert‐scale survey to evaluate their perceptions of the experience. Results Survey responses indicated that most students felt the physical examination demonstrations improved their understanding of the clinical significance of the related anatomy, increased their interest in and motivation to learn the material, and made the laboratory experience more enjoyable. Conclusions Introducing musculoskeletal physical examination skills in the gross anatomy course can be an effective way to emphasize the clinical significance of the anatomy, thereby enhancing students’ motivation to learn the material.

BackgroundTo operationalize the National Institute on Aging – Alzheimer's Association (NIA‐AA) Research Framework for Alzheimer's Disease 6‐stage continuum of clinical progression for persons with abnormal amyloid.MethodsThe Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross‐sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.ResultsAmong 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44–59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short‐term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).InterpretationThe frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145–1156

Abstract Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system, with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors presents opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from patient-derived xenografts (PDX) harboring mutant IDH-1 (R132H). Perfusates were collected from intra-cranial tumors in athymic nude mice sampled at baseline and 72h post treatment with temozolomide (TMZ), an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment. Perfusates were analyzed via untargeted metabolomic profiling using liquid chromatography-mass spectrometry. Tumor specific metabolites such as (D)-2 hydroxyglutarate, were detected in microdialysate from IDH-1 mutant tumor bearing mice compared to non-tumor bearing mice. We also found high levels of metabolites such as 5-methylthioadenosine, and dimethylarginine and wide range of amino acids in microdialysate from IDH-1 mutant tumor bearing mice. TMZ treatment induced changes to metabolites in creatine and histidine metabolism. Our results indicate that microdialysis is a feasible technology to identify metabolomics-based biomarkers in IDH1-mutant gliomas and their response to therapy. We suggest that in vivo intratumoral microdialysis over several days could yield metabolic pharmacodynamic biomarkers of value to therapeutic translation for IDH-mutant gliomas.

Abstract BACKGROUND NAD+ is required for cell metabolism and DNA repair. It is generated from nicotinic acid (NA) by NAPRT and from Nicotinamide (NAM) by NAMPT. D2HG in IDH-mutant tumors methylates and inactivates NAPRT, increasing dependence on NAMPT. Toxic side effects of NAMPT inhibition can be prevented by NA supplementation in healthy cells without NAPRT methylation. A1326133 is a recently described CNS-penetrant NAMPT inhibitor hypothesized to selectively eliminate IDH-mutant NAPRT-methylated gliomas, likely in combination with other therapies. Our group is looking for biomarkers of drug efficacy to augment individualized therapies. To that end, we sought to identify GBM cell lines with varying sensitivity to NAMPT inhibition. METHODS Human non-immortalized astrocytes and human GBM cell lines were utilized from the Mayo Clinic Glioma patient-derived xenograft resource, including IDH-R132Hmutant lines (GBM164, 196) and IDH-WT lines (GBM6, 12, 76). Cell viability was analyzed after 4days incubation with the NAMPT inhibitor, A1326133 +/- Temozolomide (TMZ) or NA. IC50 for A1326133 was estimated based on intracellular ATP using Cell-Titer-Glo. RESULTS Marked heterogeneity between lines was observed in response to A1326133 +/- NA or TMZ. Sensitive and resistant lines were identified among both IDH-mutant and IDH-WT cell lines. IC50s: GBM164, 12, 6, 196 and 76 were 5.6, 9.3, 39.2, 910, and 9455nM, respectively. NA partially rescued GBM164 by NA (IC50 increased to 20.8nM) but not GBM6 nor 12. IC50 for Human astrocytes was 221.7nM, but &gt;10,000nM with NA. Addition of TMZ did not improve A1326133 efficacy. CONCLUSION Our data illustrate the potential utility of NAMPT inhibition to kill a subset of IDH-WT and IDH mutant lines, but conflict with previously reported TMZ synergy and correlation with mutant IDH. NA may increase safety but could decrease efficacy in certain lines. Ongoing studies seek metabolic biomarkers of therapeutic efficacy to guide individualized therapy with NAMPT inhibitors.

ABSTRACTThere is a high prevalence of blood-borne infections in West Africa. This study sought to determine the seroprevalence of blood-borne infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and syphilis, in blood donors in Burkina Faso. Blood donors were recruited from 2009 to 2013 in four major cities in Burkina Faso of urban area (Ouagadougou) and rural area (Bobo Dioulasso, Fada N’Gourma, and Ouahigouya). Serology tests including hepatitis B surface antigen, anti-HCV, anti-HIV, and rapid plasma reagin test were used for screening and were confirmed with ELISA. Disease prevalence was calculated among first-time donors. Incidence and residual risk were calculated from repeat donors. There were 166,681 donors; 43,084 had ≥ 2 donations. The overall seroprevalence of HBV, HCV, HIV, and syphilis were 13.4%, 6.9%, 2.1%, and 2.4%, respectively. The incidence rates (IRs) of HBV, HCV, HIV, and syphilis infection were 2,433, 3,056, 1,121, and 1,287 per 100,000 person-years. There was lower seroprevalence of HBV and HCV in urban area than in rural area (12.9% versus 14.0%, P < 0.001; and 5.9% versus 8.0%, P < 0.001), and no difference in HIV (2.1% versus 2.1%, P = 0.25). The IRs of new HBV, HCV, HIV, and syphilis were 2.43, 3.06, 1.12, and 1.29 per 100,000 person-years, respectively. The residual risk was one per 268 donations for HBV, one per 181 donations for HCV, and one per 1,480 donations for HIV, respectively. In conclusion, this comprehensive study from four blood donation sites in Burkina Faso showed high HBV and HCV seroprevalence and incidence with high residual risk from blood donation.