In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greaterâ thanâ normal 1/T1 that is quenchable with antioxidant as measured by quenchâ assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proofâ ofâ concept data in models of ADâ like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. ADâ like models showed an abnormal gradient along the CA1 dorsalâ ventral axis of excessive free radical production as measured by Quest MRI, and redoxâ sensitive calcium dysregulation as measured by manganeseâ enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subâ field oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.â Berkowitz, B. A., Lenning J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafieâ Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017). www.fasebj.orgâ Berkowitz, Bruce A., Lenning, Jacob, Khetarpal, Nikita, Tran, Catherine, Wu, Johnny Y., Berri, Ali M., Dernay, Kristin, Haacke, E. Mark, Shafieâ Khorassani, Fatema, Podolsky, Robert H., Gant, John C., Maimaiti, Shaniya, Thibault, Olivier, Murphy, Geoffrey G., Bennett, Brian M., Roberts, Robin, In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154241/1/fsb2fj201700229r.pd

PEARL: Pharmacy Education Applied to Resident Learners

Introduction: Emergency medicine residents typically train with the support of emergency medicine pharmacists (EMP), but many EM residents will practice in post-graduation settings without EMP assistance. Therefore, a novel pharmacy curriculum for postgraduate year-1 (PGY-1) EMRs was developed, implemented, and assessed.  Methods: We performed a controlled study of 25 residents from two separate EM programs in Detroit, MI. One program was the control group and the other program was the intervention group. The primary outcome was pre- and post-curriculum knowledge assessment scores, and the secondary outcome was pre- and post-curriculum, self-perceived knowledge survey responses. We performed statistical analyses with Welch’s t-test or the Mann-Whitney U test. Results: The pre-curriculum assessment scores (41% ± 11; 41% ± 8.1; P = 0.96; mean ± SD) and average pre-curriculum survey responses (2.8 ± 0.92; 3.0 ± 0.60; P = 0.35) were not statistically different between the control and the intervention groups. The post-curriculum assessment scores (63% ± 14; 74% ± 8.3; P = 0.04) and the average post-curriculum survey responses (4.2 ± 0.61; 5.0 ± 0.74, P = 0.02) were statistically different. The increase from the pre- to post-curriculum assessment scores (24% ± 11; 33% ± 11; P = 0.05) was also significantly different.  Conclusion: The implementation of a novel pharmacy curriculum for PGY-1 EM residents resulted in improved knowledge of and comfort with pharmaceuticals and therapeutics specific to EM practice. The impact on patient care and frequency of medical errors requires further investigation

Point-of-care echocardiography of the right heart improves acute heart failure risk stratification for low-risk patients: The REED-AHF prospective study

Objectives: Validated acute heart failure (AHF) clinical decision instruments (CDI) insufficiently identify low-risk patients meriting consideration of outpatient treatment. While pilot data show that tricuspid annulus plane systolic excursion (TAPSE) is associated with adverse events, no AHF CDI currently incorporates point-of-care echocardiography (POCecho). We evaluated whether TAPSE adds incremental risk stratification value to an existing CDI. Methods: Prospectively enrolled patients at two urban-academic EDs had POCechos obtained before or <1 h after first intravenous diuresis, positive pressure ventilation, and/or nitroglycerin. STEMI and cardiogenic shock were excluded. AHF diagnosis was adjudicated by double-blind expert review. TAPSE, with an a priori cutoff of ≥17 mm, was our primary measure. Secondary measures included eight additional right heart and six left heart POCecho parameters. STRATIFY is a validated CDI predicting 30-day death/cardiopulmonary resuscitation, mechanical cardiac support, intubation, new/emergent dialysis, and acute myocardial infarction or coronary revascularization in ED AHF patients. Full (STRATIFY + POCecho variable) and reduced (STRATIFY alone) logistic regression models were fit to calculate adjusted odds ratios (aOR), category-free net reclassification index (NRIcont ), ΔSensitivity (NRIevents ), and ΔSpecificity (NRInonevents ). Random forest assessed variable importance. To benchmark risk prediction to standard of care, ΔSensitivity and ΔSpecificity were evaluated at risk thresholds more conservative/lower than the actual outcome rate in discharged patients. Results: A total of 84/120 enrolled patients met inclusion and diagnostic adjudication criteria. Nineteen percent experiencing the primary outcome had higher STRATIFY scores compared to those event free (233 vs. 212, p = 0.009). Five right heart (TAPSE, TAPSE/PASP, TAPSE/RVDD, RV-FAC, fwRVLS) and no left heart measures improved prediction (p < 0.05) adjusted for STRATIFY. Right heart measures also had higher variable importance. TAPSE ≥ 17 mm plus STRATIFY improved prediction versus STRATIFY alone (aOR 0.24, 95% confidence interval [CI] 0.06-0.91; NRIcont 0.71, 95% CI 0.22-1.19), and specificity improved by 6%-32% (p < 0.05) at risk thresholds more conservative than the standard-of-care benchmark without missing any additional events. Conclusions: TAPSE increased detection of low-risk AHF patients, after use of a validated CDI, at risk thresholds more conservative than standard of care

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease