Ma\u27ii and Nanaboozhoo Fistfight in Heaven

In the form of a cute, cuddly, and innocent waabooz, Nanaboozhoo munched on the chewy, bitter Tłohdá’ákáłiitsoh he found everywhere in this⁣ land, far from his own. Although, it was a bit dry. In this land, Dinétah,⁣ Nanaboozhoo thought he could see forever. There were few trees. The sky⁣ was bright blue and limitless. The air smelled like a kind of dirt he had never⁣ experienced. And, boy howdy, was it dry. He couldn’t smell water for the⁣ life of him. But there was water, to be sure, or else there wouldn’t be this⁣ bush

Measuring the Effect of USCG Port Security Advisory Notices On Trade and Port Security Procedures

Overview: The United States Coast Guard’s International Port Security (IPS) Program is the primary port security assessment office and was established in 2003 as part of the U.S. Maritime Transportation Security Act (MTSA) to reduce risks to U.S. ports and ships, and to the entire maritime transport system. Through the assessment of International Ship and Port Facility Security Code implementation and other measures in foreign ports, the International Port Security Program can determine whether or not there is a reasonable and acceptable level of port security at any given foreign port. This report is comprised of qualitative and quantitative research along with two case studies that compare and contrast two countries and/or ports that either succeeded or failed in complying with this program and received a Port Security Advisory (PSA). Hypothesis: Port Security Advisories (PSA) are issued when a port does not meet the International Port Security Program code. They are an instrument to build and sustain port security practices and improvements. PSAs can give standard regulations for those who use ports in compliance with a PSA as well as create maritime security protocols for other countries that do not have strong port standards. As for the economic impacts, there can be both positive and negative factors depending on the country and the situation. However, we hypothesize that overall, PSAs do not significantly influence a country’s volume of trade. Due to non-compliant countries in reporting, there is no discernable method for tracking or ensuring restrictions. Methodology: We will observe quantitative measures of trade to identify negative impacts associated with the issuance of PSAs. We will also look at quantitative data to identify positive impacts associated with PSAs. We will be using USCG’s HOMEPORT website to identify the PSAs and use COMTRADE to examine trade both before and after a PSA was issued. Trade will be compared to similar countries, those which have not received a PSA. Lastly, we will go over local and regional factors and determine what is currently working and what needs to be improved. Conclusions: Our conclusion is that as a system the PSA process is not necessary an influence on trade. There may be correlations between countries with PSAs issued and changes in trade but there are a myriad of other factors that can impact this making the current methodology less than definitive. There also may be certain countries and/or ports where the correlation appears stronger (See Case Study #1); but overall, our conclusion is that PSAs have a negligible impact on a country receiving them in influencing their volume of trade

FLNC Gene Splice Mutations Cause Dilated\ua0Cardiomyopathy

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM

Ma\u27ii and Nanaboozhoo Fistfight in Heaven

In the form of a cute, cuddly, and innocent waabooz, Nanaboozhoo munched on the chewy, bitter Tłohdá’ákáłiitsoh he found everywhere in this⁣ land, far from his own. Although, it was a bit dry. In this land, Dinétah,⁣ Nanaboozhoo thought he could see forever. There were few trees. The sky⁣ was bright blue and limitless. The air smelled like a kind of dirt he had never⁣ experienced. And, boy howdy, was it dry. He couldn’t smell water for the⁣ life of him. But there was water, to be sure, or else there wouldn’t be this⁣ bush

A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies

8siTitin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.openopenGigli, Marta; Begay, Rene L; Morea, Gaetano; Graw, Sharon L; Sinagra, Gianfranco; Taylor, Matthew R G; Granzier, Henk; Mestroni, LuisaGigli, Marta; Begay, Rene L; Morea, Gaetano; Graw, Sharon L; Sinagra, Gianfranco; Taylor, Matthew R. G; Granzier, Henk; Mestroni, Luis

Racial/Ethnic Distribution of Graduates from Doctorate and Masters Epidemiology Degree Programs in the United States, 2008 to 2018.

PURPOSE: To identify trends in racial and ethnic diversity of epidemiology graduate degree recipients in the U.S. between academic years 2008 to 2018. METHODS: National-level data from the National Center for Education Statistics was analyzed to assess the change in proportions of epidemiology degrees conferred to each racial/ethnic group - American Indian or Alaska Native; Asian, Native Hawaiian or Other Pacific Islander; Black or African American; Hispanic or Latino; White; and two or more races- over two time periods, Fall 2007- Spring 2012 (Period 1) and Fall 2012 - Spring 2018 (Period 2). RESULTS: During Period 1, 3837 epidemiology graduate degrees were conferred, and 6960 in Period 2. Within race/ethnicity groups, there was a statistically significant increase in graduate epidemiology degrees awarded over the two time periods to students of Hispanic or Latino ethnicity, and to students reporting two or more races. The proportion of degrees awarded to non-White students in aggregate increased by 4.7 percentage points, from 33.5% to 38.2%, while awards to White students decreased by the same amount. CONCLUSIONS: Overall, the racial/ethnic diversity of epidemiology graduates in the U.S. increased between 2008 and 2018, however, further efforts are needed to increase awards within some racial minority subgroups

Real-world data to evaluate effects of a multi-level dissemination strategy on access, outcomes, and equity of monoclonal antibodies for COVID-19

Abstract Introduction: Multi-level dissemination strategies are needed to increase equitable access to effective treatment for high-risk outpatients with COVID-19, particularly among patients from disproportionately affected communities. Yet assessing population-level impact of such strategies can be challenging. Methods: In collaboration with key contributors in Colorado, we conducted a retrospective cohort study to evaluate a multi-level dissemination strategy for neutralizing monoclonal antibody (mAb) treatment. Real-world data included county-level, de-identified output from a statewide mAb referral registry linked with publicly available epidemiological data. Outcomes included weekly number of mAb referrals, unique referring clinicians, and COVID-19 hospitalization rates. We assessed weekly changes in outcomes after dissemination strategies launched in July 2021. Results: Overall, mAb referrals increased from a weekly average of 3.0 to 15.5, with an increase of 1.3 to 42.1 additional referrals per county in each post-period week (p < .05). Number of referring clinicians increased from a weekly average of 2.2 to 9.7, with an additional 1.5 to 22.2 unique referring clinicians observed per county per week beginning 5 weeks post-launch (p < .001). Larger effects were observed in communities specifically prioritized by the dissemination strategies. There were no observed differences in COVID-19 hospitalization rates between counties with and without mAb treatment sites. Conclusion: Real-world data can be used to estimate population impact of multi-level dissemination strategies. The launch of these strategies corresponded with increases in mAb referrals, but no apparent population-level effects on hospitalization outcomes. Strengths of this analytic approach include pragmatism and efficiency, whereas limitations include inability to control for other contemporaneous trends

Biomass smoke inhalation promotes neuroinflammatory and metabolomic temporal changes in the hippocampus of female mice

Abstract Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m3. Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31Hi and CD31Med expressors, with wood smoke inhalation causing an increased proportion of CD31Hi. These populations of CD31Hi and CD31Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b+/CD45low) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD+ metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD+ abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure

Role of Titin Missense Variants in Dilated Cardiomyopathy

BACKGROUND-\u2014The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. METHODS AND RESULTS-\u2014A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 \u201csevere\u201d rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN \u201csevere\u201d variants). Segregation analysis allowed the classification of the \u201csevere\u201d variants into 5 \u201clikely\u201d (cosegregating), 5 \u201cunlikely\u201d (noncosegregating), and 34 \u201cpossibly\u201d (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying \u201clikely\u201d or \u201cpossibly\u201d pathogenic TTN \u201csevere\u201d variants did not show a different outcome compared with \u201cunlikely\u201d and noncarriers of a \u201csevere\u201d TTN variant. However, the \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere. CONCLUSIONS-\u2014TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically \u201csevere\u201d TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants suggests a potential biological role for some TTN missense variants

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM